Thiazine derivatives and preparation thereof

ABSTRACT

Thiazine derivatives of the formula [I]: ##STR1## wherein R 1  and R 2  are both H or form a naphthalene ring together with the benzene ring; R 3  and R 4  are both H, or one of them is halogen and another is H; X is S or O; R 5  and R 6  are each i) H, ii) lower alkyl, iii) cycloalkyl, iv) substituted phenyl, v) naphthyl, vi) lower alkyl which is substituted by substituted or unsubstituted phenyl, or vii) S-containing heterocyclic group; one of Z 1  and Z 2  is O and another is H 2  ; A is lower alkylene; R 7  and R 8  are each i) H, ii) lower alkyl, iii) lower alkenyl, iv) lower alkynyl, or v) lower alkyl which is substituted by substituted or unsubstituted phenyl, or both form together N-containing heterocyclic group; provided that when both of R 1  and R 2  are H, Z 2  is O and either one of R 5  and R 6  is substituted phenyl, naphthyl or S-containing heterocyclic group, or their salts, which have calcium antagonistic activity within the cerebral tissues and are useful for prophylaxis and treatment of ischemic encephalopathia and/or cerebral neurocyte dyscrasia, and process for preparing said compounds.

This application is a divisional of copending application Ser. No.07/648,891, filed on Jan. 31, 1991 now U.S. Pat. No. 5,246,929, theentire contents of which are hereby incorporated by reference.

TECHNICAL FIELD

This invention relates to novel thiazine (or oxazine) derivatives usefulfor the prophylaxis and treatment of ischemic encephalopathia and/orcerebral neurocyte dyscrasia, and processes for preparing the same.

PRIOR ART

Hemokinetic dyscrasia due to intracephalic hemorrhage or thromboemboliainduces shortage of glucose and oxygen etc. which are source of energyfor neurocytic activity and then induces nervous cellular necrosis atthe ischemic lesion site. For treating such ischemic encephalopathia,there has hitherto been used a medicament such as flunarizinedihydrochloride which can increase cerebral blood flow and can promotesupplement of glucose and oxygen etc. to the ischemic lesion site.

Besides, it has recently been clarified that calcium participates incellular injury in ischemia and that the cellular injury in ischemia canbe prevented by inhibiting the flow of calcium into neurocytes (cf.Trends in Pharmacological Science, 1989, 10, 397). Thus, it has beendesired very much to develop a calcium antagonistic agent which candirectly act on the cerebral cells.

SUMMARY DESCRIPTION OF THE INVENTION

An object of this invention is to provide novel compounds which haveexcellent calcium antagonistic activity within the cerebral tissues andare useful for the prophylaxis and treatment of ischemic encephalopathiaand/or cerebral neurocyte dyscrasia.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention are thiazine (or oxazine)derivative of the following formula [I]: ##STR2## wherein R¹ and R² areboth hydrogen atom or form a naphthalene ring together with the benzenering; R³ and R⁴ are both hydrogen atom, or one of them is a halogen atomand another is hydrogen atom; X is sufur atom or oxygen atom; R⁵ and R⁶are the same or different and are each i) hydrogen atom, ii) a loweralkyl, iii) a cycloalkyl, iv) a substituted phenyl, v) naphthyl, vi) alower alkyl which is substituted by a substituted or unsubstitutedphenyl, or vii) a sulfur-containing monoheterocyclic group; one of Z¹and Z² is oxygen atom and another is two hydrogen atoms; A is a loweralkylene; R⁷ and R⁸ are the same or different and are each i) hydrogenatom, ii) a lower alkyl, iii) a lower alkenyl, iv) a lower alkynyl, orv) a lower alkyl which is substituted by a substituted or unsubstitutedphenyl, or both form together with the adjacent nitrogen atom anitrogen-containing monoheterocyclic group; provided that when both ofR¹ and R² are hydrogen atom, Z² is oxygen atom and either one of R⁵ andR⁶ is a substituted phenyl, naphthyl or a sulfur-containingmonoheterocyclic group, or a pharmaceutically acceptable salt thereof.

In the compounds of the formula [I], the lower alkyl, lower alkylene andlower alkoxy denotes an alkyl, alkylene and alkoxy group having 1 to 6carbon atoms, preferably 1 to 4 carbon atoms. The lower alkenyl andalkynyl denotes an alkenyl or alkynyl group having 2 to 6 carbon atoms,preferably 2 to 4 carbon atoms. The cycloalkyl denotes a cycloalkylgroup having 3 to 8 carbon atoms, preferably 5 to 6 carbon atoms. Thesulfur-containing monoheterocyclic group includes, for example, thienylgroup, and the subsituted phenyl includes a phenyl group which issubstituted by one or two substituents selected from a halogen atom, atrihalogeno(lower)alkyl, a lower alkyl and a lower alkoxy, for example,a halogenophenyl, a dihalogenophenyl, a trihalogeno(lower)alkylphenyl, alower alkylphenyl, a lower alkoxyphenyl, or di(lower alkoxy)phenyl. Thenitrogen-containing monoheterocyclic group includes, for example,imidazolyl, morpholinyl, pyrrolidinyl, piperidinyl, and piperazinyl.

Preferred compounds are compounds of the formula [I] wherein R³ and R⁴are both hydrogen atom; one of R⁵ and R⁶ is hydrogen atom and another isa halogenophenyl, a trihalogeno(lower)alkylphenyl; A is methylene orethylene; X is sulfur atom; R⁷ and R⁸ are the same or different and areeach a lower alkyl.

The compounds [I] of this invention can be prepared by the followingprocesses.

(a) Process A

compounds [I] are prepared by reacting a compound of the formula:##STR3## wherein R¹, R², R³, R⁴, R⁵, R⁶, X and Z¹ are as defined above,or a salt thereof with a compound of the formula:

    Y.sup.2 --C(Z.sup.2)--A--Y.sup.1                           [III]

wherein Y¹ and Y² are the same or different and are each a reactiveresidue, and A and Z² are as defined above, to give a compound of theformula: ##STR4## wherein R¹, R², R³, R⁴, R⁵, R⁶, X, A, Z¹, Z², and Y¹are as defined above, and then reacting the above compound [IV] with anamine compound of the formula: ##STR5## wherein R⁷ and R⁸ are as definedabove, or a salt thereof.

(b) Process B

The compounds [I] are prepared by reacting the compound of the formula[II] or a salt thereof with a compound of the formula: ##STR6## whereinY³ is a reactive residue, and Z², A, R⁷ and R⁸ are as defined above.

(c) Process C

The compounds [I] wherein A is ethylene, Z¹ is two hydrogen atom, and Z²is oxygen atom are prepared by reacting the compound of the formula [II]or a salt thereof with an acrylic acid compound of the formula:

    Y.sup.2 --CO--CH═CH.sub.2                              [VII]

wherein Y² is as defined above, to give a compound of the formula:##STR7## wherein R¹, R², R³, R⁴, R⁵, R⁶, and X are as defined above, andthen reacting the above compound [VIII] with an amine compound [V].

(d) Process D

The compounds [I] wherein at least one of R⁷ and R⁸ is a lower alkyl, alower alkenyl, a lower alkynyl, or a lower alkyl which is substituted bya substituted or unsubstituted phenyl are prepared by reacting acompound of the formula: ##STR8## wherein R¹, R², R³, R⁴, R⁵, R⁶, X, A,Z¹, and Z² are as defined above, and R⁷¹ is hydrogen atom, a loweralkyl, a lower alkenyl, a lower alkynyl, or a lower alkyl which issubstituted by a substituted or unsubstituted phenyl, or a salt thereofwith a compound of the formula:

    R.sup.81 --Y.sup.4                                         [IX]

wherein R⁸¹ is a lower alkyl, a lower alkenyl, a lower alkynyl, or alower alkyl which is substituted by a substituted or unsubstitutedphenyl, and Y⁴ is a reactive residue.

In the above reactions, the starting compounds of the formulae [II], [V]and [VI] and the compounds of the formula [I-a] may be used in a freeform or in the form of a conventional acid addition salt such as mineralacid salts or organic acid salts. The reactive residues Y¹, Y², Y³ andY⁴ includes, for example, a halogen atom (e.g. chlorine atom, bromineatom, etc.), a lower alkylsulfonyloxy, or a loweralkylphenylsulfonyloxy.

The condensation reaction between the compound [II] and the compound[III], the compound [VI], or the acrylic acid compound [VII], and thecondensation reaction between the compound [I-a] and the compound [IX]can be carried out in an appropriate solvent in the presence of a base.These reactions proceed at a temperature of from cooling temperature toelevated temperature, preferably 0° to 100° C.

The reaction between the compound [IV] or the compound [VIII] and theamine compound [V] can be carried out in the presence or absence of abase in an appropriate solvent or without solvent. This reactionproceeds at a temperature of from cooling temperature to elevatedtemperature, preferably 0° to 100° C.

The base used in the above reactions includes any conventional bases,preferably tri(lower alkyl)amines, N-lower alkylmorpholines,N,N-di(lower alkyl)anilines, pyridine, alkali metal hydrogen carbonates,alkali metal carbonates, and the like.

The solvent used in the above reactions includes any conventional inertsolvents, preferably acetone, toluene tetrahydrofuran, dioxane,methylene chloride, chloroform, dimethylformamide, dimethyl sulfoxide,methanol, ethanol, and the like.

In case of Z¹ being two hydrogen atoms, the above reaction proceedswithout racemization, and hence, when an optically active startingcompound wherein Z¹ is two hydrogen atoms is used, there can be obtainedan optically active compound [I].

Besides, the compounds [I] can optionally be subjected to opticalresolution to give each optically active compounds [I]. The resolvingagent may be any conventional resolving agents and further includes anoptically active3-[(5-chloro-2-nitrophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionicacid. For instance, an optically active compound [I] can be obtained byreacting a racemic compound [I] with a resolving agent to form adiastereomer salt, dividing the salt into each isomer by the differenceof solubility in a solvent, followed by treating with a basic substance.

The desired compounds [I] of this invention may be used in a free formor in the form of a pharmaceutically acceptable salt. Thepharmaceutically acceptable salt includes inorganic acid salts [e.g.hydrochloride, hydrobromide, sulfate, etc.), or organic acid additionsalts (e.g. oxalate, fumarate, maleate, etc.).

The compounds [I] of this invention include also the optical isomersowing to the asymmetric carbon at 2-position of the thiazine or oxazinering and also a mixture of the isomers.

The compounds [I] or pharmaceutically acceptable salts thereof of thisinvention can be administered orally or parenterally to a warm-bloodedanimal, including human being, and can be used in a conventionalpharmaceutical preparation, such as tablets, granules, capsules,powders, injections, and the like.

The dosage of the compounds [I] or pharmaceutically acceptable saltsthereof of this invention may vary depending on the administrationroute, age, weight and state of patient, severity of diseases, and thelike, but is usually in a range of about 0.1 to 100 mg/kg per day,preferably about 3 to 30 mg/kg per day.

The starting compounds [II] include novel compounds of the formula:##STR9## wherein X' is sulfur atom or oxygen atom; R⁵¹ and R⁶¹ are thesame or different and are each i) hydrogen atom, ii) a lower alkyl, iii)a cycloalkyl, iv) a substituted phenyl, v) naphthyl, vi) a lower alkylwhich is substituted by a substituted or unsubstituted phenyl, or vii) asulfur-containing monoheterocyclic group; Z¹¹ is oxygen atom or twohydrogen atoms; provided that when Z¹¹ is two hydrogen atoms and R⁵¹ andR⁶¹ are both hydrogen atom, X' is sulfur atom, which can be prepared bythe following processes.

The compounds [II-a] wherein Z¹¹ is oxygen atom can be prepared byreacting a compound of the formula: ##STR10## wherein X' is as definedabove, with a compound of the formula: ##STR11## wherein Y⁵ is a halogenatom, Y⁶ is a halogen atom or a lower alkoxy, and R⁵¹ and R⁶¹ are asdefined above, in the presence or absence of a base (e.g. sodiumacetate, potassium hydroxide, etc.), and when a compound of the formula:##STR12## wherein R⁵¹, R⁶¹, X', and Y⁵ are as defined above, isobtained, and the above compound [XII] is further subjected to aring-closing reaction in the presence of a base (e.g. potassiumcarbonate, etc.).

The compounds [II-a] wherein Z¹¹ is oxygen atom, and one of R⁵¹ and R⁶¹is hydrogen atom and other is a substituted phenyl, naphthyl, a loweralkyl which is substituted by a substituted or unsubstituted phenyl or asulfur-containing monoheterocyclic group can be prepared by halogenatinga compound of the formula: ##STR13## wherein X' is as defined above,then reacting the resulting 3-halogenated compound with a compoundselected from a substituted benzene, naphthalene and a sulfur-containingmonoheterocyclic compound in the presence of a Lewis acid (e.g. stannicchloride, etc.), or reacting the compound [XIII] with a substituted orunsubstituted benzaldehyde compound in the presence of a base (e.g.sodium methoxide, etc.), followed by subjecting to catalytic reductionwith a catalyst (e.g. palladium on charcoal, etc.).

Besides, the compounds [II-a] wherein Z¹¹ is two hydrogen atoms can beprepared by reducing the corresponding compounds [II-a] wherein Z¹¹ isoxygen atom in the presence of a reducing agent (e.g. alkali metalborohydride, diborane, etc.).

Another starting compounds [II] can also be prepared from acorresponding substituted or unsubstituted 2-amino(thio)phenol or acorresponding substituted or unsubstituted 1-amino-2-naphthol (ornaphthalenethiol) in accordance with the procedure desclosed above.

Activities

The activities of the compounds of this invention were tested.

Experiment 1

Activity against entrance of calcium into cerebral synaptosome:

A cerebral synaptosome suspension was prepared from the cerebral cortexof rat in accordance with the procedure disclosed in The Journal ofPhysiology, 1989, 387, pages 415-423. To the suspension were added afluorescent reagent (cf. "Note" hereinbelow) and a solution of testdrug, and thereto was further added potassium chloride to depolarize.The fluorescent strength of the mixture was measured at 500 nm whenirradiating mutually UV rays of wavelength of 340 nm and 380 nm with anapparatus for measuring intracellular calcium (CAF-100, manufactured byNippon Bunko K.K.). The activity of the test drug for inhibiting theentrance of calcium into the synaptosome was calculated based on therate of specific change (ΔR) of fluorescent strength at peak by thefollowing equation. As a control, dimethylsulfoxide was used instead ofthe test drug. ##EQU1## wherein R=fluorescent strength at 340nm/fluorescent strength at 380 nm.

[Note]: The fluorescentreagent=1-(2-(5'-carboxyoxazol-2'-yl]-6-aminobenzofuran-5-oxy)-2-(2'-amino-5'-methylphenoxy)ethane-N,N,N',N'-tetraaceticacid pentaacetoxymethyl ester (tradename, Fura 2-MA, manufactured byDojin Kenkyusho).

Results

When the compounds as shown in the following Table 1 were used as thetest drug in a concentration of 10⁻⁵ M, these compounds showed theinhibitory activity of calcium entrance as shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    Test compound:                                                                 ##STR14##                                             Inhibitory rate                                                              of calcium entrace      No.                                                                              R.sup.1                                                                           R.sup.2                                                                           R.sup.5      Z.sup.1                                                                          Z.sup.2                                                                         A      NR.sup.7 R.sup.8  (%)                     __________________________________________________________________________        ##STR15##                                                                             ##STR16##   H.sub.2                                                                          O CH.sub.2                                                                              ##STR17##        69.8                    2                                                                                 ##STR18##                                                                             ##STR19##   H.sub.2                                                                          O CH.sub.2                                                                              ##STR20##        54.2                    3                                                                                 ##STR21##                                                                             ##STR22##   O  H.sub.2                                                                         CH.sub.2 CH.sub.2                                                                     ##STR23##        59.6                    4                                                                                 ##STR24##                                                                             ##STR25##   O  H.sub.2                                                                         CH.sub.2 CH.sub.2                                                                     ##STR26##        67.0                    5  H   H                                                                                  ##STR27##   H.sub.2                                                                          O CH.sub.2                                                                              ##STR28##        70.1                    6                                                                                 ##STR29##                                                                             ##STR30##   H.sub.2                                                                          O CH.sub.2                                                                              ##STR31##        55.6                    7                                                                                 ##STR32##                                                                             ##STR33##   H.sub.2                                                                          O CH.sub.2                                                                              ##STR34##        54.2                    8                                                                                 ##STR35##                                                                             ##STR36##   H.sub.2                                                                          O CH.sub.2                                                                              ##STR37##        56.2                    9                                                                                 ##STR38##                                                                             ##STR39##   O  H.sub.2                                                                         CH.sub.2 CH.sub.2                                                                     ##STR40##        51.8                    10                                                                                ##STR41##                                                                             ##STR42##   O  H.sub.2                                                                         CH.sub.2 CH.sub.2                                                                     ##STR43##        53.4                    __________________________________________________________________________

Experiment 2

Activity for protecting cerebral anoxia inuded by potassium cyanide:

The test drug was orally administered to mice. One hour after theadministration, potassium cyanide (2.4 mg/kg) was administered into thetail vein, and the survival time (second) of the mice was measured. Onthe basis of the average survival time in the medicated group and thecontrol group, the rate of prolonging of the survival time wascalculated by the following equation. In the control group, distilledwater was administered instead of the test drug. ##EQU2##

Results

When the compounds as shown in the following Table 2 were orallyadministered as the test drug in a dose of 10 mg/kg, these compoundsshowed the prolonging rate of survival time as shown in Tables 2A and2B.

                                      TABLE 2A                                    __________________________________________________________________________    Test compound:                                                                 ##STR44##                                Prolonging rate                                                              of survival time                     No.                                                                              R.sup.1                                                                           R.sup.2                                                                           R.sup.5  Z.sup.1                                                                         Z.sup.2                                                                         A      R.sup.7                                                                            R.sup.8                                                                            (%)                                  __________________________________________________________________________    1  H   H                                                                                  ##STR45##                                                                             H.sub.2                                                                         O CH.sub.2                                                                             C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    62                                       ##STR46##                                                                             ##STR47##                                                                             H.sub.2                                                                         O CH.sub.2                                                                             CH.sub.3                                                                           CH.sub.3                                                                           49                                   3                                                                                 ##STR48##                                                                             ##STR49##                                                                             H.sub.2                                                                         O CH.sub.2                                                                             C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    65                                   4                                                                                 ##STR50##                                                                             ##STR51##                                                                             O H.sub.2                                                                         CH.sub.2                                                                             CH.sub.3                                                                           CH.sub.3                                                                           62                                   5                                                                                 ##STR52##                                                                             ##STR53##                                                                             O H.sub.2                                                                         CH.sub.2 CH.sub.2                                                                    CH.sub.3                                                                           CH.sub.3                                                                           56                                   6  H   H                                                                                  ##STR54##                                                                             H.sub.2                                                                         O CH.sub.2                                                                             C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    48                                   __________________________________________________________________________

                  TABLE 2B                                                        ______________________________________                                        Test compound:                                                                 ##STR55##                Prolonging rate                                                              of survival time                                     No.   X    R.sup.5 R.sup.6                                                                             R.sup.7                                                                              R.sup.8                                                                              (%)                                    ______________________________________                                        7    S     CH.sub.3                                                                              CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                      42                                     8    O     H       H     CH.sub.3                                                                             CH.sub.3                                                                             93                                     ______________________________________                                    

The compounds (I) of this invention can inhibit the calcium entranceinto the cerebral synaptosome and show excellent central calciumantagonistic activity and/or excellent calcium antagonistic activity incerebral blood vessel, and can be used for the treatment and prophylaxisof cerebral diseases due to cerebral blood flow disorder at acute andchronic periods, for example, subarachnoid hemorrhage, cerebralinfarction, etc. The compounds (I) of this invention have also anactivity for protecting cerebral neurocyte. For example, when2-(4-chlorophenyl)-4-(diethylamino)acetyl-3,4-dihydro-2H-1,4-benzothiazinewas intraperitoneally administered to evanescent cerebral ischemic ratswith ligating four vessels in a dose of 1.5 mg/kg twice a day for fourdays, it increased the number of normal pyramidal cells at hippocampulCA₁ region in about 90% in comparison with the non-medicated group.Accordingly, the compounds (I) of this invention can effectively be usedfor the prophylaxis, treatment and amelioration of sequelae of cerebralneurocyte dyscrasia, for example, disturbances of consciousness (e.g.somnolenz, sopor, coma, stupor, clouding of consciousness, etc.), motorparalysis (e.g. parkinsonism, etc.), cerebral neuropathy (e.g. dysuria,etc.), speech and language disorders (e.g. articulation disorders,aphasia, semantic aphasia, etc.), sensitive disorders (e.g. pain,sysesthesia, heat sensibility disorder, etc.), psychological disorders(e.g. dementia, hallucination, delusion, delirium, poriomania,melancholia, neurosis, emotional incontinence, etc.), and the like, andfurther the prophylaxis of palindromia and also the prophylaxis ofexacerbation and progression of the symptoms. Moreover, the compounds(I) of this invention show little activity to heart and circular organsand hence has characteristics of direct action onto the cerebral cells.In addition, the compounds (I) of this invention have low toxicity andhas high safety. For example, when the compounds of this invention suchas2-(4-chlorophenyl)-4-(diethylamino)acetyl-3,4-dihydro-2H-1,4-benzothiazineoxalate,3-(4-chlorophenyl)-1-(diethylamino)acetyl-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazineoxalate, and1-[3-(dimethylamino)propyl]-3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]thaizin-2[3H]-one oxalate were orally administered to mice ina dose o 500 mg/kg, no mouse died even after 7 days.

EXAMPLES

The compounds of this invention is illustrated by the following Examplesbut should not be construed to be limited thereto.

EXAMPLE 1

(1) To a mixture of2-(4-fluorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (4.0 g),sodium borohydride (2.91 g) and tetrahydrofuran (100 ml) is addeddropwise with stirring boron trifluoride etherate complex (12. 5 ml) atroom temperature, and the mixture is refluxed for 1.5 hour. Aftercooling, to the mixture is added dropwise 10% hydrochloric acid (35 ml),and the mixture is further refluxed for one hour. The reaction mixtureis poured into ice water and made alkaline with potassium carbonate andextracted with ethyl acetate. The ethyl acetate layer is washed, driedand distilled to remove the solvent. The residue is recrystallized fromisopropyl ether to give2-(4-fluorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (3.45 g, yield 91%)as crystals.

M.p. 134°-135.5° C.

(2) To a solution of the compound obtained above (2.60 g) andtriethylamine (3.6 ml) in methylene chloride (45 ml) is added dropwise asolution of chloroacetyl chloride (1.70 ml) in methylene chloride (5 ml)under ice cooling, and the mixture is stirred at room temperature forone hour. After the solvent is distilled off, to the residue are addedethyl acetate and water, and the ethyl acetate layer is washed withwater, dried and distilled to remove the solvent. The residue isrecrystallized from isoporpyl ether to give4-chloroacetyl-2-(4-fluorophenyl)-3,4-dihyro-2H-1,4-benzothiazine (3.02g, yield 89%).

M.p. 122°-123.5° C.

(3) To a solution of the compound obtained above (1.20 g) intetrahydrofuran (15 ml) is added a 15% solution of dimethylamine inmethanol (15 ml), and the mixture is stirred at room temperature for 20hours. The solvent is distilled off, and to the residue are added ethylacetate and aqueous sodium hyrogen carbonate solution. The ethyl acetatelayer is washed, dried, and distilled to remove the solvent. The residueis dissolved in ethanol-ether and thereto is added one equivalent ofoxalic acid. The resulting precipitate is recrystallized fromethanol-ether to give4-(dimethylamino)acetyl-2-(4-fluorophenyl)-3,4-dihydro-2H-1,4-benzothiazineoxalate (1.45g, yield 93%).

M.p. 171.5°-172.5° C.

EXAMPLES 2 TO 17

(1) The corresponding starting materials are treated in the same manneras described in Example 1-(1) to give the compounds as shown in Tables 3and 4.

                  TABLE 3                                                         ______________________________________                                         ##STR56##                                                                    Compd.                                                                        symbol R.sup.2                                                                             R.sup.3                                                                             X    M.p. (solvent for recrystal.)                         ______________________________________                                        A      H     Cl    S    139-142° C. (isopropyl ether)                  B      H     H     O     99-100° C. (isopropyl ether-n-hexane)         ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                                ##STR57##                                                             Compd.                                                                        symbol R.sup.5       M.p. (solvent for recrystal.) etc.                       ______________________________________                                                ##STR58##    74-75° C. (n-hexane)                              D                                                                                     ##STR59##    101.5-103° C. (isopropyl ether-n- hexane)         E                                                                                     ##STR60##    84-89° C. (ethyl acetate-n- hexane)               F                                                                                     ##STR61##    93-95° C. (ethyl acetate-n- hexane)               G                                                                                     ##STR62##    110-112° C. (ethyl acetate-n- hexane)             ______________________________________                                    

(2) The compounds obtained in the above (1) or corresponding compoundsare reacted with chloroacetyl chloride in the same manner as describedin Example 1-(2) to give the compounds as shown in Tables 5 and 6.

                  TABLE 5                                                         ______________________________________                                                ##STR63##                                                             Compd.                                                                        symbol R.sup.2                                                                             R.sup.3                                                                             X   M.p. (solvent for recrystal.) etc.                     ______________________________________                                        A      H     Cl    S   119.5-121° C. (ethyl acetate-n-hexane)          B      H     H     O   caramel,                                                                      MS (m/z): 321 (M.sup.+), IR ν.sub.max.sup.Neat                             (cm.sup.-1):                                                                  1670                                                   ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                                ##STR64##                                                             Compd.                                                                        symbol R.sup.5        M.p. (solvent for recrystal.) etc.                      ______________________________________                                                ##STR65##     104-105.5° C. (ethyl acetate-n- hexane)          D                                                                                     ##STR66##     133-135.5° C. (ethanol)                          E                                                                                     ##STR67##     93-97° C. (ethanol)                              F                                                                                     ##STR68##     caramel, MS (m/z): 371 (M.sup.+), IR                                          ν.sub.max.sup.CHCl.sbsp.3 (cm.sup.-1): 1670          G                                                                                     ##STR69##     121-123° C. (isopropyl ether)                    H                                                                                     ##STR70##     94-95° C. (ethanol)                              I                                                                                     ##STR71##     110-112° C. (ether)                              ______________________________________                                    

(3) The compounds of the above (2) or the compound in Example 1-(2) arereacted with the corresponding amine compound in the same manner asdescribed in Example 1-(3) to give the compounds as shown in Tables 7 to9.

                  TABLE 7                                                         ______________________________________                                                 ##STR72##                                                            Ex.                                                                           No.     R.sup.2                                                                             R.sup.3 M.p. (solvent for recrystal.)                           ______________________________________                                        2       H     Cl      Oxalate: 162-163.5° C. (ethanol-ether)           ______________________________________                                    

                                      TABLE 8                                     __________________________________________________________________________     ##STR73##                                                                     No.Ex.                                                                           R.sup.5                                                                                  ##STR74##                                                                          M.p. (solvent for recrystal.) etc.                        __________________________________________________________________________        ##STR75## N(C.sub.2 H.sub.5).sub.2                                                           65-68° C. (isopropyl ether-n-hexane) oxa- late:                        143-144° C. (dec.) (methanol-ether)                 4                                                                                 ##STR76## N(C.sub.2 H.sub.5).sub.2                                                           oxalate: 180-182° C. (ethanol)                      5                                                                                 ##STR77## N(C.sub.2 H.sub.5).sub.2                                                           oxalate: 111-113° C. (dec.) (ethanol-ether)         6                                                                                 ##STR78## N(C.sub.2 H.sub.5).sub.2                                                           oxalate: 146-148° C. (dec.) (ethanol-ether)         7                                                                                 ##STR79## N(C.sub.2 H.sub.5).sub. 2                                                          oxalate: 166.5-167.5° C. (dec.) (ethanol-                              ether)                                                     8                                                                                 ##STR80## N(CH.sub.3).sub.2                                                                  oxalate: 192-194° C. (dec.) (ethanol-ether)         9                                                                                 ##STR81## N(C.sub.2 H.sub.5).sub.2                                                           oxalate: 177-179° C. (ethanol-ether)                10                                                                                ##STR82## N(C.sub.2 H.sub.5).sub.2                                                           oxalate: 161-163° C. (ethanol-ether)                __________________________________________________________________________

                  TABLE 9                                                         ______________________________________                                         ##STR83##                                                                     No.Ex.                                                                             X                                                                                   ##STR84##            recrystal.) etc.M.p. (solvent                ______________________________________                                                                        for                                           11   S     N(CH.sub.3).sub.2    hydrochloride:                                                                253.5-255.5° C.                                                        (dec.) (ethanol-                                                              ether)                                        12   S                                                                                    ##STR85##           oxalate: 177- 179° C. (dec.)                                           (ethanol-ether)                               13   S                                                                                    ##STR86##           oxalate: 197.5- 198.5° C. (dec.)                                       (methanol)                                    14   O     N(CH.sub.3).sub.2    oxalate: 211-                                                                 213° C. (dec.)                                                         (methanol-ether)                              15   O     N(C.sub.2 H.sub.5).sub.2                                                                           oxalate: 144-                                                                 146° C. (dec.)                                                         (ethanol-ether)                               16   S     NHCH.sub.3           oxalate: 225-                                                                 227° C. (dec.)                                                         (methanol)                                    17   S                                                                                    ##STR87##           oxalate: powder MS (m/z): 498, 496                                            (M.sup.+), 345 IR ν.sub.max.sup.Nujol                                      (cm.sup.-1): 1720, 1670                       ______________________________________                                    

EXAMPLE 18

(1) To a mixture of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine(9.62 g), sodium hydrogen carbonate (6.0 g), methylene chloride (100 ml)and water (50 ml) is added dropwise with stirring a solution of acryloylchloride (5.0 g) in methylene chloride (20 ml) under ice cooling over aperiod of about 30 minutes. The mixture is stirred at room temperaturefor 3 hours, and the organic layer is washed and dried. After thesolvent is distilled off, the resulting crystals are washed withn-hexane to give2-(4-chlorophenyl)-4-acryloyl-3,4-dihyro-2H-1,4-benzothiazine (10.76 g,yield 93%).

M.p. 122°-124° C.

(2) To a suspension of the compound obtained above (2.21 g) in ethanol(50 ml) is added a 31% solution of dimethylamine in ethanol (20 ml), andthe mixture is stirred at room temperature for one hour. The solvent isdistilled off, and to the residue is added hydrogen chloride-ethanol.Ethanol is distilled off, and the residue is recrystallized fromethanol-ether to give2-(4-chlorophenyl)-4-[3-(dimethylamino)propionyl]-3,4-dihydro-2H-1,4-benzothiazinehydrochloride (2.13 g, yield 77%).

M.p. 188°-190° C.

EXAMPLE 19

The corresponding starting material is treated in the same manner asdescribed in Example 18-(2) to give the compound as shown in Table 10.

                  TABLE 10                                                        ______________________________________                                         ##STR88##                                                                     No.Ex.                                                                              ##STR89##                                                                               M.p. (solvent for recrystal.)                                ______________________________________                                        19    N(C.sub.2 H.sub.5).sub.2                                                                hydrochloride: 191-194° C. (ethanol-ether)             ______________________________________                                    

EXAMPLE 20

To a solution of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine(0.52 g) ad N,N-dimethylaniline (0.97 g) in methylene chloride (15 ml)is added dimethylaminoacetyl chloride hydrochloride (0.63 g) under icecooling, and the mixture is stirred at the same temperature for 2.5hours. To the reaction mixture is added aqueous sodium hydrogencarbonate solution, and is extracted with chloroform. The chloroformlayer is washed, dried and distilled to remove the solvent. The residueis treated with hydrochloric acid and the resulting salt isrecrystallized from ethanol-ether to give2-(4-chlorophenyl)-4-(dimethylamino)acetyl-3,4-dihyro-2H-1,4-benzothiazinehydrochloride (0.63 g, yield 86%).

M.p. 253°-255° C. (dec.)

EXAMPLE 21

A mixture of 2-(4-chlorophenyl)-4-(N-methylaminoacetyl)-3,4-dihydro-2H1,4-benzothiazine (1.80 g), allyl bromide (0.52 ml), potassium carbonate(2.25 g) and dimethylformamide (20 ml) is stirred at room temperaturefor 3.5 hours. The reaction mixture is poured into water, and themixture is extracted with ethyl acetate. After the solvent is distilledoff, the residue is purified by silica gel column chromatography(solvent, chloroform: methanol=40:1). The caramel thus obtained isdissolved in ether and thereto is added 1.1 equivalent of oxalic acid.The resulting precipitate is washed with ether and dried to give4-(N-allyl-N-methylaminoacetyl)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazineoxalate as powder.

Mass (m/z): 374, 372 (M⁺)

IR ν_(max) ^(Nujol) (cm⁻¹): 1720, 1680

EXAMPLE 22

2-(4-Chlorophenyl)-4-(N-methylaminoacetyl)-3,4-dihyro-2H-1,4-benzothiazineand 2-propynyl bromide are treated in the same manner as described inExample 21 to give4-[N-(2-propynyl)-N-methylaminoacetyl]-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazineoxalate.

M.p. 169.5°-171° C. (dec.) (recrystallized from ethanol-ether).

EXAMPLE 23

(1) To a mixture of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine(1.08 g), ethyl acetate (20 ml) and aqueous sodium hydrogen carbonatesolution (20 ml) is added dropwise a solution of 4-bromobutyryl chloride(0.97 g) in ethyl acetate (5 ml) with stirring under ice cooling. Theethyl acetate layer is washed, dried and distilled to remove thesolvent. The residue is recrystallized from ethyl acetate-n-hexane togive4-(4-bromobutyryl)-2-(4-chlorophenyl)-3,4-dihyro-2H-1,4-benzothiazine(1.58 g, yield 93%).

M.p. 91°-92° C.

(2) To a solution of the compound obtained above (1.19 g) intetrahydrofuran (5 ml) is added a 20% solution of dimethylamine intetrahydrofuran (5 ml), and the mixture is stirred at room temperaturefor 5 hours. After the reaction is completed, the solvent is distilledoff, and to the residue are added ethyl acetate and aqueous sodiumhydrogen carbonate solution. The ethyl acetate layer is washed, dried,and distilled to remove the solvent. The oily residue is dissolved inethanol and thereto is added oxalic acid (0.22 g). The resultingprecipitate is recrystallized from ethanol-ether to give2-(4-chlorophenyl)-4-[4-(dimethylamino)butanoyl]-3,4-dihydro-2H-1,4-benzothiazineoxalate (1.03 g, yield 76%).

M.p. 170°-170.5° C. (dec.)

EXAMPLE 24

To a solution of 1-amino-2-naphthalenethiol (27.81 g) in ethanol (500ml) is added sodium borohydride (11.35 g) at room temperature. Themixture is stirred for 20 minutes, and thereto is added dropwise aceticacid (200 ml) and is further added sodium acetate (24.6 g). To themixture is further added dropwise methyl α-bromo-4-chlorophenylacetate(46.8 g), and the mixture is sitrred at room temperature under argonovernight. The reaction mixture is poured into ice water and theresulting precipitate is separated by filtration, washed, dried andrecrystallized from tetrahydrofuran-n-hexane to give3-(4-chlorphenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (44.45 g,yield 82.6%) as crystals.

M.p. 235.5°-237.5° C.

EXAMPLES 25 TO 31

The corresponding starting materials are treated in the same manner asdescribed in Example 24 to give the compounds as shown in Table 11.

                  TABLE 11                                                        ______________________________________                                         ##STR90##                                                                    Ex.                                                                           No.    R.sup.5  R.sup.6      M.p. (°C.)                                ______________________________________                                        25A    H        H            200-201° C. *1                            25B    CH.sub.3 CH.sub.3     182-183° C. *2                            26     H                                                                                       ##STR91##   192-194° C. *1                            27     H                                                                                       ##STR92##     250-252.5° C. *1                        28     H                                                                                       ##STR93##   244-246° C. *1                            29     H                                                                                       ##STR94##   251-253° C. *1                            30     H                                                                                       ##STR95##   203.5-206° C. *1                          31     H                                                                                       ##STR96##   233-235° C. *1                            ______________________________________                                         *1 Recrystallized from tetrahydrofuranhexane                                  *2 Recrystallized from tetrahydrofuranisopropyl ether                    

EXAMPLE 32

To a mixture of 1-amino-2-naphthol (9.4 g), N,N-dimethylaniline (17.87g) and tetrahydrofuran (160 ml) is added dropwiseα-bromo-4-chlorophenylacetyl chloride (18.97 g) under ice cooling, andthe mixture is stirred for one hour. To the reaction mixture is addedethyl acetate, and the ethyl acetate layer is washed, dried anddistilled to remove the solvent. The resulting oil is dissolved inacetone (500 ml) and thereto is added potassium carbonate (40.8 g), andthe mixture is refluxed for 2 hours, and acetone is distilled off. Tothe residue is added water, and the precipitate is separated byfiltration, washed, dried and recrystallized from tetrahyrofuran to give3-(4-chlorophenyl)-1H-naphtho[2,1-b][1,4]oxazin 2(3H)-one (13.29 g,yield 72.8%).

M.p. 230.5°-232° C.

EXAMPLE 33

1-Amino-2-naphthol and bromoacetyl chloride are reacted in the samemanner as described in Example 32 to give1H-naphthol[2,1-b][1,4]oxazin-2(3H)-one

M.p. 219°-220.5° C. (recrystallized from tetrahydrofuran)

EXAMPLE 34

To a solution of3-(4-chlorophenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (38.45 g) andsodium borohydride (22.32 g) in tetrahydrofuran (1.0 liter) is addeddropwise with stirring boron trifluoride etherate complex (100 ml) atroom temperature, and the mixture is refluxed for 2 hours. Aftercooling, to the mixture are added methanol (200 ml), 10 hydrochloricacid (300 ml) and conc. hydrochloric acid (150 ml) in this order and themixture is further refluxed for 4 hours. To the reaction mixture isadded ice water and the mixture is made alkaline with potassiumcarbonate and extracted with ethyl acetate. The ethyl acetate layer iswashed, dried and distilled to remove the solvent. The residue isrecrystallized from tetrahydrofuran-n-hexane to give3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (32.3 g,yield 88%) as crystals.

M.p. 185°-186.5° C.

EXAMPLES 35 TO 44

The compounds obtained in Examples 25 to 33 are treated in the samemanner as described in Example 34 to give the compounds as shown inTable 12.

                  TABLE 12                                                        ______________________________________                                         ##STR97##                                                                    Ex.                                                                           No.   X     R.sup.5  R.sup.6     M.p. (°C.)                            ______________________________________                                        35    S     H        H           102-104° C. *2                        36    S     CH.sub.3 CH.sub.3    125-128° C. *2                        37    S     H                                                                                       ##STR98##  135.5-136.5° C. *2                    38    S     H                                                                                       ##STR99##    159-160.5° C. *2                    39    S     H                                                                                       ##STR100## 203-206° C. *2                        40A   S     H                                                                                       ##STR101## 174-176° C. *2                        40B   S     H                                                                                       ##STR102## 180-182° C. *2                        41    S     H                                                                                       ##STR103## 137-139° C. *2                        42    S     H                                                                                       ##STR104## 156-158° C. *2                        43    O     H                                                                                       ##STR105## 168-170° C. *1                        44    O     H        H           hydrochloride:                                                                211-214° C. *3                        ______________________________________                                         *1 Recrystallized from tetrahydrofuranhexane                                  *2 Recrystallized from ethyl acetaten-hexane                                  *3 Recrystallized from ethanol                                                [Note]:                                                                       The compound of Example 44 is disclosed in Journal of the Chemical Societ     Vol. 121, page 647.                                                      

EXAMPLE 45

(1) To a suspension of3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (14.09 g)and triethylamine (13.7 g) in methylene chloride (300 ml) is addeddropwise chloroacetyl chloride (10.2 g) under ice cooling. After themixture is stirred at room temperature for one hour, the reactionmixture is washed, dried and distilled off to remove the solvent. Theresidue is crystallized from isopropyl ether to give1-chloroacetyl-3-(4-chlorophenyl)-2,3-dihyro-1H-naphtho[2,1-b][1,4]thiazine(15.45 g, yield 88%).

M.p. 172°-174° C.

(2) To a suspension of the compound obtained above (15.45 g) and sodiumiodide (13.6 g) in tetrahydrofuran (100 ml) is added diethylamine (80ml). After the mixture is stirred at room temperature for 2 hours, thesolvent and diethylamine are distilled off, and to the residue are addedethyl acetate and aqueous sodium hydrogen carbonate solution. The ethylacetate layer is washed, dried, and concentrated to give3-(4-chlorophenyl)-1-(diethylamino)acetyl-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(17.0 g) as an oil. The product is dissolved in ethanol and thereto isadded one equivalent of fumaric acid. The resulting precipitate isrecrystallized from 1% aqueous acetone to give3-(4-chlorophenyl)-1-(diethylamino)acetyl-2,3-dihydro-1H-naphtho[2,1-b][1.4]-thiazinefumarate (17.45 g, yield 81%).

M.p. 164.5°-166° C.

EXAMPLES 46 TO 54

(1) The compounds obtained in Examples 35 to 44 are reacted withchloroacetyl chloride in the same manner as described in Example (45-(1)to give the compounds as shown in Table 13.

                  TABLE 13                                                        ______________________________________                                         ##STR106##                                                                   Ex. No.                                                                              X     R.sup.5                                                                              R.sup.6    Physical properties, etc.                      ______________________________________                                        46(1)  S     CH.sub.3                                                                             CH.sub.3                                                                                  ##STR107##                                    47(1)  S     H                                                                                     ##STR108##                                                                                m.p. 156-157.5° C. *2                 48(1)  S     H                                                                                     ##STR109##                                                                              m.p. 139-141° C. *3                     49(1)  S     H                                                                                     ##STR110##                                                                              m.p. 178-180° C. *4                     50(1)  S     H                                                                                     ##STR111##                                                                              m.p. 125-127° C. *4                     51(1)  S     H                                                                                     ##STR112##                                                                              m.p. 143-145° C. *4                     52(1)  S     H                                                                                     ##STR113##                                                                              m.p. 123-125° C. *4                     53(1)  O     H                                                                                     ##STR114##                                                                              m.p. 132-134° C. *3                     54(1)  O     H      H                                                                                         ##STR115##                                    ______________________________________                                         *2 Recrystallized from ethyl acetaten-hexane                                  *3 Recrystallized from ethanol                                                *4 Recrystallized from isopropyl ether                                   

(2) The products obtained in the above (1) are reacted with thecorresponding amine compounds in the same manner as described in Example45-(2) to give the compounds as shown in Tables 14 and 15.

                  TABLE 14                                                        ______________________________________                                         ##STR116##                                                                   Ex. No R.sup.5                                                                              R.sup.6      Physical properties, etc.                          ______________________________________                                        46(2)  CH.sub.3                                                                             CH.sub.3                                                                                    ##STR117##                                        47(2)  H                                                                                     ##STR118##  m.p. 167-171.5° C. (dec.) *5                48(2)  H                                                                                     ##STR119##                                                                                 ##STR120##                                        49(2)  H                                                                                     ##STR121##  m.p. 182-184° C. (dec.) *5                  50(2)  H                                                                                     ##STR122##  m.p. 145-148° C. *5   .sup.                 51(2)  H                                                                                     ##STR123##                                                                                 ##STR124##                                        52(2)  H                                                                                     ##STR125##                                                                                 ##STR126##                                        ______________________________________                                         *5 Recrystallized from ethanoldiethyl ether                              

                  TABLE 15                                                        ______________________________________                                         ##STR127##                                                                    No.Ex.                                                                             R.sup.5                                                                             R.sup.6                                                                                  ##STR128##                                                                            Physical properties, etc.                      ______________________________________                                        53(2)                                                                              H                                                                                    ##STR129##                                                                              N(C.sub.2 H.sub.5).sub.2                                                              oxalate: m.p. 168-170° C. (dec.) *5      54(2)                                                                              H     H          N(CH.sub.3).sub.2                                                                     hydrochloride:                                                                m.p. 213-215° C. (dec.)                  ______________________________________                                                                      *5                                               *5 Recrystallized from ethanoldiethyl ether                              

EXAMPLES 55 TO 65

The products obtained in Examples 34, 35, 40A, 40B, 41 to 43 are reactedwith the corresponding amine compounds in the same manner as describedin Example 45 to give the compounds as shown in Table 16.

                  TABLE 16                                                        ______________________________________                                         ##STR130##                                                                    No.Ex.                                                                             X     R.sup.5                                                                                     ##STR131##                                                                             properties, etc.Physical                   ______________________________________                                        55   S                                                                                    ##STR132##   N(CH.sub.3).sub.2                                                                      m.p. 217-219° C. (dec.) *6           56   S                                                                                    ##STR133##                                                                                  ##STR134##                                                                            m.p. 209-211° C. (dec.) *7           57   S                                                                                    ##STR135##                                                                                  ##STR136##                                                                            m.p. 234-236° C. (dec.) *7           58   S                                                                                    ##STR137##                                                                                  ##STR138##                                                                            m.p. 239-240° C.  (dec.) *7          59   S                                                                                    ##STR139##   NHCH.sub.3                                                                             m.p. 238.5-240.5° C. (dec.) *7       60   S     H             N(CH.sub.3).sub.2                                                                      m.p. 215-216° C.                                                       (dec.) *6                                   61   S                                                                                    ##STR140##   N(CH.sub.3).sub.2                                                                      m.p. 143-146° C. *5                  62   S                                                                                    ##STR141##   N(CH.sub.3).sub.2                                                                      m.p. 215-217° C. *5                  63   S                                                                                    ##STR142##   N(CH.sub.3).sub.2                                                                      m.p. 193-195° C. (dec.) *5           64   S                                                                                    ##STR143##   N(CH.sub.3).sub.2                                                                      m.p. 151-153° C. *5                  65   O                                                                                    ##STR144##   N(CH.sub.3).sub.2                                                                      m.p. 226-228° C. (dec.)              ______________________________________                                                                          *7                                           *6 Recrystallized from methanoldiethyl ether                                  *7 Recrystallized from methanol                                          

EXAMPLE 66

To a mixture of3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (0.62 g),N,N-dimethylaniline (2 ml) and methylene chloride (15 ml) is added inportions dimethylaminoacetyl chloride hydrochloride (1.26 g) under icecooling. After the mixture is stirred at room temperature for 2 hours,to the reaction mixture is added aqueous sodium hydrogen carbonatesolution, and the mixture is extracted with chloroform. The chloroformlayer is washed, dried and distilled to remove the solvent. The residueis purified by silica gel column chromatography (CHCl₃ : methanol=30:1)to give3-(4-chlorophenyl)-1-(dimethylamino)acetyl-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(0.36 g, 45%) as caramel.

The compound obtained above is dissolved in ether and thereto is addedone equivalent of oxalic acid. The resulting precipitate is separated byfiltration and is recrystallized from methanol-diethyl ether to give3-(4-chlorophenyl)-1-(dimethylamino)acetyl-2,3-dihyro-1H-naphtho[2,1-b][1,4]-thiazineoxalate.

M.p. 216°-218° C. (dec.)

EXAMPLE 67

(1) To a mixture of3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (1.50 g),sodium hydrogen carbonate (1.0 g), methylene chloride (30 ml) and water(15 ml) is added dropwise with stirring a solution of acryloyl chloride(0.90 g) in methylene chloride (10 ml) under ice cooling. The mixture isstirred at room temperature for 3 hours. The organic layer is separated,washed, dried and distilled to remove the solvent. The residue ischromatographed on silica gel (toluene: acetone=50:1) to give3-(4-chlorophenyl)-1-propenoyl-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(1.37 g, 78%) as powder.

Mass (m/z): 365 (M⁺)

IR ν_(max) ^(Nujol) (cm⁻¹); 1660, 1620

(2) To a suspension of the compound obtained above (1.33 g) intetrahydrofuran (10 ml) is added dropwise a 17% solution ofdimethylamine in methanol (15 ml). After the mixture is stirred at roomtemperature for one hour, the solvent is distilled off to give3-(4-chlorophenyl)-1-[3-(dimethylamino)propionyl]-2,3-dihyro-1H-naphtho[2,1-b][1,4]-thiazine(1.39 g) as caramel.

The compound obtained above is dissolved in ether, and thereto is addedone equivalent of oxalic acid. The resulting precipitate is separated byfiltration and recrystallized from methanol to give3-(4-chlorophenyl)-1-[3-(dimethylamino)propionyl]-2,3-dihydro-1H-naphtho[2,1-b][1,4]-thiazineoxalate.

M.p. 217°-219° C. (dec.)

EXAMPLES 69 TO 70

The corresponding starting materials are treated in the same manner asdescribed in Example 24 to give the compounds as shown in Table 17.

                  TABLE 17                                                        ______________________________________                                                ##STR145##                                                            Ex. No.  R.sup.5       R.sup.6                                                                             M.p.                                             ______________________________________                                        69       CH.sub.3      H     179.5-181° C. *1                          70                                                                                      ##STR146##   H     215.5-217.5° C. *1                        ______________________________________                                         *1 Recrystallized from tetrahydrofurann-hexane                                *8 Recrystallized from tetrahydrofurandiisopropyl ether                  

EXAMPLE 71

(1) A mixture of 1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (5.17 g),4-chlorobenzaldehyde (5.62 g), sodium methoxide (1.73 g) anddimethylformamide (80 ml) is refluxed for 4.5 hours. After cooling, thereaction mixture is poured into water and the resulting precipitate isseparated by filtration, washed and dried and then is recrystallizedfrom tetrahydrofuran-n-hexane to give3-(4-chlorobenzylidene)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (4.28g). M.p. 277°-279° C.

(2) A mixture of the compound obtained above (4.0 g), 10% palladium oncharcoal (2.0 g), tetrahydrofuran (200 ml) and ethanol (40 ml) isstirred under hydrogen gas under atmospheric pressure for 3 hours. Afterthe reaction is completed, 10% palladium-carbon is removed byfiltration, and the solvent is distilled off. The residue isrecrystallized from ethyl acetate-n-hexane to give3-(4-chlorobenzyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (3.20 g).M.p. 185°-186° C.

EXAMPLE 72

To a mixture of 1-amino-2-naphthol (16.9 g), N,N-dimethylaniline (19.3g) and tetrahydrofuran (200 ml) is added dropwise chloroacetyl chlorideunder ice cooling, and the mixture is stirred at the same temperaturefor one hour. To the reaction mixture is added ethyl acetate, and theethyl acetate layer is washed, dried and distilled to remove thesolvent. The resulting oil is dissolved in acetone (500 ml) and theretois added potassium carbonate (75 g), and the mixture is refluxed for 2hours, and acetone is distilled off. To the residue is added water, andthe precipitate is separated by filtration, washed, dried andrecrystallized from tetrahyrofuran to give1H-naphtho[2,1-b][1,4]oxazin-2(3H)-one (13.1 g). M.p. 219°-220.5° C.

EXAMPLE 73

(1) To a solution of3-(4-chlorophenyl)-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-one (10.0 g) and96% sodium hydroxide (1.96 g) in dimethylsulfoxide (150 ml) is added1-bromo-3-chloropropane (6.78 g) under ice cooling, and the mixture isstirred at room temperature overnight. The reaction mixture is pouredinto water, and the mixture is extracted with ethyl acetate. The ethylacetate layer is washed and distilled to remove the solvent. The residueis purified by silica gel column chromatography (eluent; n-hexane:ethylacetate=5:1) and further is recrystallized from methanol to give3-(4-chlorophenyl)-1-(3-chloropropyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3-H)-one(8.04 g). M.p. 110°-112.5° C.

(2) A mixture of the compound obtained above (1.0 g), diethylamine (3.72g), sodium iodide (1.5 g), potassium carbonate (1.8 g) and acetone (50ml) is refluxed overnight. The reaction mixture is distilled to removethe solvent, and to the residue is added water, and the mixture isextracted with ethyl acetate. The extract is distilled to remove thesolvent. The residue is purified by silica gel column chromatography(eluent; chloroform: methanol=20:1) to give3-(4-chlorophenyl)-1-[3-(diethylamino)propyl]-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-oneas oil.

To a solution of the compound obtained above in ether is added oneequivalent of oxalic acid, and the resulting precipitate is separated byfiltration and recrystallized from ethanol-diethyl ether to give3-(4-chlorophenyl)-1-[3-(diethylamino)propyl]-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-oneoxalate (0.75 g). M.p. 190.5°-192.5° C. (dec.)

EXAMPLES 74 TO 75

(1) The compound obtained in Example 24 is treated in the same manner asdescribed in Example 73 to give the compounds as shown in Table 18.

                  TABLE 18                                                        ______________________________________                                         ##STR147##                                                                    Ex. No.                                                                              ##STR148##   M.p. etc.                                                ______________________________________                                        74                                                                                    ##STR149##  hydrochloride: 224.5-227° C. *5                    75                                                                                    ##STR150##  oxalate: 184.5-187.5° C. (dec.)                    ______________________________________                                                            *3                                                         *3 Recrystallized from ethanol                                                *5 Recrystallized from ethanoldiethyl ether                              

EXAMPLE 76

A mixture of3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one(18.0 g), potassium carbonate (24.2 g), 3-(dimethylamino)propyl chloridehydrochloride (9.5 g), acetone (400 ml) and water (4 ml) is refluxed for48 hours. The insoluble materials are filtered off and acetone isdistilled off, and to the residue are added ethanol (200 ml) and 10%hydrochloric acid (100 ml), and the mixture is refluxed for one hour.After ethanol is distilled off and the insoluble materials are filteredoff, the resulting mixture is made alkaline with sodium hydrogencarbonate and extracted with ethyl acetate. The extract is distilled toremove the solvent to give1-[3-(dimethylamino)propyl]-3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]-thiazin-2(3H)-oneas oil.

Mass (m/z): 444 (M⁺)

To a solution of the compound obtained above in ether is added oneequivalent of oxalic acid, and the resulting precipitate is separated byfiltration and recrystallized from ethanol-diethyl ether to give1-[3-(dimethylamino)propyl]-3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-oneoxalate (16.23 g).

M.p. 130°-133° C.

EXAMPLES 77 TO 87

The compounds obtained in Examples 24, 25B, 26, 28-29, 69-72 are treatedin the same manner as described in Example 76 to give the compounds asshown in Tables 19 to 21.

                  TABLE 19                                                        ______________________________________                                         ##STR151##                                                                   Ex.                                                                           No.  R.sup.5      R.sup.6                                                                              A        M.p.                                        ______________________________________                                        77   CH.sub.3     H      (CH.sub.2).sub.3                                                                       oxalate:                                                                      163-165° C. *5                       78   CH.sub.3     CH.sub.3                                                                             (CH.sub.2).sub.3                                                                       oxalate:                                                                      169-170° C. *5                       79                                                                                  ##STR152##  H      (CH.sub.2).sub.3                                                                       oxalate: 93° C. (dec.) *9            80                                                                                  ##STR153##  H      (CH.sub.2).sub.2                                                                       oxalate: 220-221.5° C. (dec.)                                          *7                                          81                                                                                  ##STR154##  H      (CH.sub.2).sub.3                                                                       oxalate: 235-236.5° C. (dec.)                                          *6                                          82                                                                                  ##STR155##  H      (CH.sub.2).sub.3                                                                       oxalate: 190-192.5° C. (dec.)                                          *3                                          83                                                                                  ##STR156##  H      (CH.sub.2).sub.2                                                                       hydrochloride: 208.5-211.5° C.                                         *9                                          84                                                                                  ##STR157##  H      (CH.sub.2).sub.3                                                                       hydrochloride: 183-185.5° C. *5      85                                                                                  ##STR158##  H      (CH.sub.2).sub.3                                                                       hydrochloride: 219-222° C.           ______________________________________                                                                          *5                                           *3 Recrystallized from ethanol                                                *5 Recrystallized from ethanoldiethyl ether                                   *6 Recrystallized from methanoldiethyl ether                                  *7 Recrystallized from methanol                                               *9 Recrystallized from ethyl acetate                                     

                  TABLE 20                                                        ______________________________________                                         ##STR159##                                                                     No.Ex.                                                                            R.sup.5       A                                                                                       ##STR160##                                                                            M.p.                                    ______________________________________                                         86                                                                                 ##STR161##   (CH.sub.2).sub.3                                                                         ##STR162##                                                                           174-176° C. (dec.)                ______________________________________                                                                             *3                                        *3 Recrystallized from ethanol                                           

                  TABLE 21                                                        ______________________________________                                                    ##STR163##                                                        Ex. No.      R.sup.5                                                                              M.p.                                                      ______________________________________                                        87           H      136.5-139.5° C. *5                                 ______________________________________                                         *5 Recrystallized from ethanoldiethyl ether                              

EXAMPLES 88

To a mixture of3-(4-chlorophenyl)-1-[3-(methylamino)propyl]-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one(1.79 g), potassium carbonate (2.18 g) and acetone (50 ml) is addedallyl bromide (0.65 g) under ice cooling, and the mixture is stirred atroom temperature overnight. The insoluble materials are filtered off andacetone is distilled off, and the oily residue is purified by silica gelcolumn chromatography (eluent, chloroform: methanol=20:1) to give1-[3-(N-allyl-N-methylamino)propyl]-3-(4-chlorophenyl)-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-oneas oil.

To a solution of the compound obtained above in ether is added oneequivalent of oxalic acid, and the resulting precipitate is separated byfiltration and recrystallized from ethanol-diethyl ether to give 1[3-(N-allyl-N-methylamino)-propyl]-3-(4-chlorophenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-oneoxalate (1.52 g).

M.p. 172.5°-175.5° C. (dec.)

EXAMPLE 89

The compound obtained in Example 74 is treated in the same manner asdescribed in Example 88 to give3-(4-chlorophenyl)-1-{3-[N-methyl-N-(2-propynyl)amino]propyl}-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-one.

Oxalate: m.p. 166°-169° C. (dec., recrystallized from ethanol-diethylether).

EXAMPLE 90

(1) To a solution of(±)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (10.01 g, 0.038mole) in pyridine (150 ml) is added (S)-N-(2-naphthalenesulfonyl)prolylchloride (18.57 g, 0.057 mole), and the mixture is stirred at roomtemperature for 4 hours. To the reaction mixture is added ethyl acetate,and the mixture is washed with 5% hydrochloric acid, water, aqueoussodium hydrogen carbonate solution, water and saline in this order, andthe ethyl acetate layer is separated, dried over sodium sulfate anddistilled to remove the solvent. The resulting caramel is subjected tosilica gel column chromatography (hexane:ethyl acetate=5:1-3:1). Fromthe fraction eluted first there is obtained(R)-2-(4-chlorophenyl)-4-[(S)-N-(2-naphthalenesulfonyl)prolyl]-3,4-dihydro2H-1,4-benzothiazine (10.75 g, 51%) as crystals. M.p. 147°-151° C.

Besides, from the fraction eluted subsequently there is obtained(S)-2-(4-chlorophenyl)-4-[(S)-N-(2-naphthalene-sulfonyl)prolyl]-3,4-dihydro-2H-1,4-benzothiazine(7.58 g, 36%) as crystals. M.p. 171°-174.5° C.

(2)(R)-2-(4-Chlorophenyl)-4-[(S)-N-(2-naphthalene-sulfonyl)prolyl]-3,4-dihydro-2H-1,4-benzothiazine(9.40 g, 0.017 mole) is suspended in ethanol-water (10:1, 188 ml), andthereto is added 86% potassium hydroxide (11.2 g, 0.172 mole), and themixture is refluxed for 30 minutes. The reaction mixture is poured intoice water and the mixture is extracted with ethyl acetate. The ethylacetate layer is washed with water and saline, dried over sodium sulfateand distilled to remove the solvent. The residue is purified by silicagel column chromatography (CHCl₃) and thereafter recrystallized fromethyl acetate-hexane twice to give(R)-(+)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (2.61 g,58%).

M.p. 151°-153° C. [α]_(D) ²⁰ +38.0° (c=1.0, CHCl₃).

In the same manner as described above,(S)-2-(4-chlorophenyl)-4-[(S)-N-(2-naphthalenesulfonyl)prolyl]-3,4-dihydro-2H-1,4-benzothiazine(7.26 g, 0.0132 mole) is treated to give(S)-(-)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (2.45 g,71%). M.p. 151°-152.5° C.

[α]_(D) ²⁰ -38.4° (c=1.0, CHCl₃).

(3) To a suspension of(R)-(+)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.30 g,0.005 mole) and triethylamine (1.66 ml, 0.012 mole) in dichloromethane(16 ml) is added dropwise a solution of chloroacetyl chloride (0.79 ml,0.01 mole) in dichloromethane (4 ml) under ice cooling, and the mixtureis stirred at room temperature for 45 minutes. After the solvent isdistilled off, to the residue are added ethyl acetate and water, and theethyl acetate layer is washed with aqueous sodium hydrogen carbonatesolution, water and saline, dried over sodium sulfate and distilled toremove the solvent to give(R)-4-chloroacetyl-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine(1.84 g) as caramel.

A mixture of the above-obtained compound, diethylamine (8 ml), sodiumiodide (1.49 g, 0.01 mole) and tetrahydrofuran (24 ml) is stirred atroom temperature for 30 minutes, and the volatiles are distilled off. Tothe residue are added ethyl acetate and aqueous sodium hydrogencarbonate solution, and the ethyl acetate layer is washed with water andsaline, dried over sodium sulfate and distilled to remove the solvent.The residue is purified by silica gel column chromatography (CHCl₃ :methanol=50:1) to give(R)-(+)-2-(4-chlorophenyl)-4-diethylaminoacetyl-3,4-dihydro-2H-1,4-benzothiazine(1.74 g, 94%) as caramel. Mass (m/z): 376, 374 (M⁺)

Oxalate (recrystallized from ethanol):

M.p. 133°-135° C. (decomp.)

[α]_(D) ²⁰ +111.9° (c=1.0, H₂ O).

In the same manner as described above,(S)-(-)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.30 g,0.005 mole) is treated to give(S)-(-)-2-(4-chlorophenyl)-4-diethylaminoacetyl-3,4-dihydro-2H-1,4-benzothiazine(1.72 g, 92%) as caramel. Mass (m/z) 376, 374 (M⁺)

Oxalate (recrystallized from ethanol):

M.p. 133°-135° C. (decomp.)

[α]_(D) ²⁰ -112.6° (c=1.0, H₂)).

EXAMPLE 91

(±)-2-(4-Chlorophenyl)-4-diethylaminoacetyl-3,4-dihydro-2H-1,4-benzothiazine(68.54 g, 0.183 mole) and (2S,3S)-3-[(5-chloro-2-nitrophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionicacid (70.16 g, 0.183 mole) are dissolved in ethyl acetate (one liter),and the mixture is concentrated to about 500 ml and then allowed tostand. The resulting precipitate is separated by filtration andrecrystallized from ethyl acetate twice to give a salt of (R)-isomer(30.80 g) as crystals. M.p. 153°-154° C.

The above-obtained compound is treated with diethyl ether-aqueous sodiumhydrogen carbonate solution to convert into free base. The product istreated with HCl-ethanol to convert into hydrochloride. This product isrecrystallized from ethanol-diethyl ether to give(R)-(+)-2-(4-chlorophenyl)-4-diethylaminoacetyl-3,4-dihydro-2H-1,4-benzothiazinehydrochloride (12.88 g, 17%) as crystals.

M.p. 211.5°-212.5° C.

[α]_(D) ²⁰ +128.6° (c=1.0, H₂ O)

In the same manner as described above except that (2R,3R)-3-[(5-chloro-2-nitrophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionicacid is used as the resoluting agent, there is obtained(S)-(-)-2-(4-chlorophenyl)-4-diethylaminoacetyl-3,4-dihydro-2H-1,4-benzothiazinehydrochloride.

M.p. 211°-212.5° C.

[α]_(D) ²⁰ -126.5° (c=1.0, H₂ O)

EXAMPLE 92

(1) A mixture of3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (25.0 g,0.080mole), (S)-N-(2-naphthalenesulfonyl)propyl chloride (25.96 g, 0.080mole) and benzene (800 ml) is stirred at 60° C. for 24 hours. Theinsoluble materials are removed by filtration, and to the filtrate isadded ethyl acetate, and the mixture is washed with 5% hydrochloricacid, water, aqueous sodium hydrogen carbonate solution, water andsaline in this order, and the ethyl acetate layer is dried over sodiumsulfate and distilled to remove the solvent. The residue is subjected tosilica gel column chromatography (ethyl acetate: hexane=1:3). From thefraction eluted first there is obtained(R)-3-(4-chlorophenyl)-1-[(S)-N-(2-naphthalenesulfonyl)prolyl]-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (11.97 g, 25%) as caramel.

Mass (m/z): 600, 598 (M⁺)

IR ν_(max) ^(neat) cm⁻¹ :1680

Besides, from the fraction eluted subsequently there is obtained(S)-3-(4-chlorophenyl)-1-[(S)-N-(2-naphthalenesulfonyl)prolyl]-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(12.13 g, 25.3%) as crystals. M.p. 204°-205° C.

(2) A mixture of(R)-3-(4-chlorophenyl)-1-[(S)-N-(2-naphthalenesulfonyl)prolyl]-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(11.50 g, 0.019 mole), 86% potassium hydroxide (15.0 g, 0.227 mole) andethanol-water (10:1, 230 ml) is refluxed under argon for one hour. Thereaction mixture is poured into ice water and the mixture is extractedwith ethyl acetate. The ethyl acetate layer is washed with water andsaline, dried over sodium sulfate and distilled to remove the solvent.The residue is purified by silica gel column chromatography (CHCl₃) andthereafter recrystallized from ethyl acetate-hexane to give(R)-(+)-3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(3.74 g, 63%).

M.p. 205°-206° C.

[α]_(D) ²⁰ +121.7° (c=1.0, CHCl₃).

In the same manner as described above,(S)-3-(4-chlorophenyl)-1-[(S)-N-(2-naphthalenesulfonyl)prolyl]-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(11.50 g, 0.019 mole) is treated to give(S)-(-)-3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(3.09 g, 52%).

M.p. 206°-207° C.

[α]_(D) ²⁰ -121.1° (c=1.0, CHCl₃).

(3) To a suspension of(R)-(+)-3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(2.0 g, 0.0064 mole) and triethylamine (2.1 ml, 0.015 mole) indichloromethane (30 ml) is added dropwise a solution of chloroacetylchloride (1.0 ml, 0.0126 mole) in dichloromethane (5 ml) under icecooling, and the mixture is stirred at room temperature for 45 minutes.After the volatiles are distilled off, to the residue are added ethylacetate and water, and the ethyl acetate layer is washed with aqueoussodium hydrogen carbonate solution, water and saline, dried over sodiumsulfate and distilled to remove the solvent. The residue is purified bysilica gel column chromatography (ethyl acetate: hexane=1:4) to give(R)-1chloroacetyl-3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(2.40 g, 96%) as caramel.

A mixture of the above-obtained compound (1.20 g, 0.0031 mole), sodiumiodide (0.93 g, 0.0062 mole) and 10% solution of dimethylamine intetrahydrofuran (25 ml) is stirred at room temperature for 5.5 hours,and the solvent is distilled off. To the residue are added ethyl acetateand aqueous sodium hydrogen carbonate solution, and the ethyl acetatelayer is washed with water and saline, dried over sodium sulfate anddistilled to remove the solvent. The residue is purified by silica gelcolumn chromatography (CHCl₃ methanol=50:1) to give(R)-(+)-3-(4-chlorophenyl)-1-dimethylaminoacetyl-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(1.15 g, 94%) as caramel. Mass (m/z): 398, 396 (M⁺)

Oxalate (recrystallized from methanol-diethyl ether):

M.p. 215.5°-216.5° C. (decomp.)

[α]_(D) ²⁰ +297.0° (c=1.0, DMF)

In the same manner as described above,(S)-(-)-3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine(0.98 g, 0.0031 mole) is treated to give(S)-(-)-3-(4-chlorophenyl)-1-dimethylaminoacetyl-2,3-dihydro-1H-naphtho[2,1-b][1,4]-thiazine(1.19 g, 95.0%) as caramel. Mass (m/z): 398, 396 (M⁺)

Oxalate (recrystallized from methanol-diethyl ether):

M.p. 215°-216.5° C. (decomp.)

[α]_(D) ²⁰ -296.6° (c=1.0, DMF)

EXAMPLE 93

The corresponding starting material is treated in the same manner asdescribed in Example 92, there is obtained (R)-(+)-and (S)-(-)-3(4-chlorophenyl)-1-diethylaminoacetyl-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazineoxalate.

(R)-(+)-isomer (oxalate: recrystallized from acetone):

M.p. 137°-140° C.

[α]_(D) ²⁰ +322.7° (c=1.0, methanol)

(S)-(-)-isomer (oxalate: recrystallized from acetone):

M.p. 138°-140.5° C.

[α]_(D) ²⁰ -321.7° (c=1.0, methanol)

EXAMPLE 94

(±)-1-Dimethylaminopropyl-3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one(7.53 g, 0.0169 mole) and (2R,3R)-3-[(5-chloro-2-nitrophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionicacid (6.50 g, 0.0169 mole) are dissolved in ethyl acetate, and themixture is concentrated and thereto is added diethyl ether, and themixture is allowed to stand overnight. The resulting precipitate isseparated by filtration and recrystallized from ethyl acetate twice togive a salt of (+)-isomer (3.04 g, 22%) as crystals. M.p. 147°-148° C.

The above-obtained compound (2.80 g) is stirred in diethyl ether-aqueoussodium hydrogen carbonate solution. The diethyl ether layer is washedwith water, dried and distilled to remove the solvent to give(+)-1-dimethylaminopropyl-3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one(1.42 g, 94%) as oil.

Mass (m/z): 444 (M⁺)

IR ν_(max) ^(neat) cm⁻¹ :1670 [α]_(D) ²⁰ +80.1°60 (c=1.0, CHCl₃).

Oxalate:

M.p. 101°-104° C.

[α]_(D) ²⁰ +115.9° (c=1.0, methanol)

In the same manner as described above except that (2S,3S)-3-[(5-chloro-2-nitrophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionicacid is used as the resolving agent, there is obtained(-)-1-dimethylaminopropyl-3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-oneas oil.

Mass (m/z) 444 (M⁺)

IR ν_(max) ^(neat) cm⁻¹ :1670

[α]_(D) ²⁰ -80.5° (c=1.0, CHCl₃).

Oxalate:

M.p. 102°-106° C.

[α]_(D) ²⁰ -118.6° (c=1.0, methanol)

[PREPARATION OF STARTING MATERIALS] REFERENCE EXAMPLE 1

To a suspension of 2-aminothiophenol (12.6 g) and o sodium acetate (23.6g) in ethanol (150 ml) is added methyl α-bromo-4-fluorophenylacetate(23.6 g), and the mixture is stirred at room temperature overnight.After the solvent is distilled off, water is added to the residue. Theresulting precipitate is separated by filtration, washed, dried, andthen recrystallized from tetrahydrofuran-n-hexane to give2-(4-fluorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (21.7 ascrystals. M.p. 216°-219° C.

REFERENCE EXAMPLES 2 TO 4

The corresponding starting materials are treated in the same manner asdescribed in Reference Example 1 to give the compounds as shown in Table22.

                  TABLE 22                                                        ______________________________________                                                ##STR164##                                                            Ref. Ex. No.                                                                           R.sup.5       M.p. (solvent for recrystal.)                          ______________________________________                                                  ##STR165##   159-161.5° C. (tetrahydrofuran-n-hexane)        3                                                                                       ##STR166##   227-229° C. (tetrahydrofuran-n-hexane)          4                                                                                       ##STR167##   199-201° C. (tetrahydrofuran-n-hexane)          ______________________________________                                    

REFERENCE EXAMPLE 5

To a solution of 2-amino-5-chlorothiophenol (4.49 g) in ethanol (30 ml)is added 96% potassium hydroxide (1.63 g), and the mixture is distilledto remove ethanol. The resulting solid material is suspended in toluene(70 ml) and thereto is added methyl α-bromo-4-chlorophenylacetate (7.38g), and the mixture is refluxed overnight. The reaction mixture isconcentrated, and the resulting precipitate is separated by filtration,washed, dried, and then recrystallized from tetrahydrofuran-n-hexane togive 7-chloro-2-(4-chlorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine(6.58 g) as crystals. M.p. 230°-233.5° C.

REFERENCE EXAMPLE 6

To a soltuion of 2-chloro-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (9.38g) and thiophene (7.91 g) in methylene chloride (250 ml) is added inportions stannic chloride (12. 2 g) at 0° to 5° C. After stirring at thesame temperature for 45 minutes, the mixture is poured into ice water,and the organic layer is separated. The aqueous layer is extracted withethyl acetate, and the ethyl acetate layer is combined with the aboveorganic layer and distilled to remove the solvent. The resulting solidmaterial is recrystallized from ethanol to give3-oxo-2-(2-thienyl)-3,4-dihydro-2H-1,4-benzothiazine (8.17 g) ascrystals.

M.p. 174°-177° C.

REFERENCE EXAMPLE 7

The corresponding starting materials are treated in the same manner asdescribed in Reference Example 6 to give the compound as shown in Table23.

                  TABLE 23                                                        ______________________________________                                                 ##STR168##                                                           Ref. Ex. No.                                                                            R.sup.5      M.p. (solvent for recrystal.)                          ______________________________________                                                   ##STR169##  246.5-247.5° C. (tetrahydrofuran-ethanol)       ______________________________________                                    

REFERENCE EXAMPLE 8

To a solution of 2-aminophenol (13.5 g) in ethyl acetate (150 ml) isadded a solution of sodium hydrogen carbonate (15 g) in water (300 ml),and to the mixture is added dropwise a solution of α-bromo-4-chlorophenylacetyl chloride (32.2 g) in toluene with vigorousstirring under ice cooling. After the mixture is stirred at roomtemperature for one hour, the solvent in the organic layer is distilledoff and the residue is dissolved in acetone. To the solution is addedpotassium carbonate (20 g), and the mixture is stirred at roomtemperature overnight. The solvent is distilled off and to the residueis added water. The mixture is extracted with ethyl acetate. The ethylacetate layer is washed, dried and distilled to remove the solvent, andthe residue is recrystallized from ethyl acetate-n-hexane to give2-(4-chlorophenyl)-3-oxo 3,4-dihyro-2H-1,4-benzoxazine (24.0 g) ascrystals. M.p. 180.5°-181.5° C.

what is claimed is:
 1. A thiazine derivative of the following formula[I]: ##STR170## wherein R¹ and R² are both hydrogen atoms; R³ and R⁴ areboth hydrogen atoms; X is a sulfur atom; R⁵ is a hydrogen atom; R⁶ ishalogeno substituted phenyl; Z¹ is two hydrogen atoms; Z² is an oxygenatoms; A is lower alkylene; R⁷ and R⁸ are the same or different and areeach lower alkyl; or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein R⁶ is chlorphenyl, and R⁷ and R⁸are both methyl or ethyl. 3.2-(4-Chlorophenyl)-4-(diethylamino)acetyl-3,4-dihydro-2H-1,4-benzothiazineor a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition which comprises a therapeutically effective amount of athiazine derivative of the formula [I] as set forth in claim 1 inadmixture of a conventional pharmaceutically acceptable carrier ordiluent.
 5. A method for the prophylaxis or treatment of ischemicencephalopathia in a warm-blooded animal which comprises administeringan effective amount of a thiazine derivative of the formula [I] as setforth in claim 1 to said warm-blooded animal suffering from the disease.